Gliederung

Background: A randomized phase III trial was performed in patients (pts) with advanced ovarian cancer (OC) to evaluate the role of TOP in first line treatment: To optimize the standard of care we included a non cross resistant third drug (TOP) in a sequential manner to the standard of care (TC), thus avoiding the toxicity of a simultaneous triple drug regimen.

Material and Methods: From 12/1999 to 03/2002 1,308 pts with previously untreated OC FIGO stage IIB–IV were randomized to receive 6 cycles of Paclitaxel (175 mg/m2 3h iv) and Carboplatin (AUC 5, Calvert formula) (TC) followed by surveillance or 4 cycles of Topotecan (1.25 mg/m2 iv d1-5) (Top) on a 3 week schedule. Pts were stratified within each center according to residual tumor size and FIGO stage: stratum 1 „FIGO stage IIB–IIIC and residual tumor ≤ 1 cm”, and stratum 2 „FIGO stage IIB–IIIC and residual tumor > 1 cm or FIGO IV“. The primary endpoint was overall survival (OS). This study was designed to demonstrate an increase in 3 year OS of 8% with a power of 80% using a two-sided stratified logrank test with alpha set to 5%. To detect this effect at least 541 events are necessary.

Results: 650 pts were assigned to TC and 658 to TC-Top. Overall, 9453 treatment cycles were administered, 5564 in the TC-Top arm and 3889 in the TC arm. 78% of pts who were randomized for Top received Top. The median number of Top courses was 4.0. G 3/4 anemia occurred in 6.4% of Top courses, thrombocytopenia in 10.7%, neutropenia in 57%. This was of minimal clinical relevance in terms of febrile neutropenia (0.9%) or infections (0.9%). Response data were available from 145 and 147 pts with measurable disease in the TC-Top and TC arm. TC-Top was associated with 69.0% CR and PR; TC with 76.2% (ns). 947 pts had progressed and 625 pts had died. Median PFS for pts with TC-Top was 18.2 months vs. 18.5 months for TC, corresponding to a HR adjusted for stratum of 0.97 (95% CI 0.85–1.10, p = 0.688). Median OS for pts with TC-Top was 43.1 months vs. 44.5 months for TC (HR adjusted for stratum = 1.01, 95% CI 0.86–1.18, p = 0.885).

Conclusions: The addition of Top to TC did not result in superior OR, PFS and OS. Therefore, TC remains standard of care.